Surgical resection is the only curative therapy for pancreatic ductal adenocarcinoma (PDAC) but is contraindicated in patients in which the disease has metastasized. Options to improve curative rates include earlier detection and/or effective therapeutic targeting of the metastatic cell population. By definition, all metastatic cancers must be able to escape the primary tumor site, survive within the circulatory system and implant and proliferate in a secondary site. Currently, in vitro systems cannot adequately mimic the changing microenvironments a migrating cell experiences as it travels from the tumor and through the circulatory system. This project is a collaborative venture between a cancer biochemist and a biomedical engineer to develop a 'PDAC-on-a-chip' that recreates the oxygen environments found both in the tumor and circulatory environment. This device, therefore, is capable of isolating the fraction of aggressive tumor cells that needs to be targeted for therapy. Cells in the 'tumor compartment' will be exposed to in vivo-like chronic or intermittent, cycling hypoxia that triggers cell motility. The motile cells can penetrate a gel barrier and 'intravasate' into a secondary oxygen-rich 'circulatory compartment' that mimics the tumor blood vessel or lymphatic system. The oxygen shock experienced by invasive cells further selects for circulation-viable cells likely equivalent to the circulating tumor cells observed in vivo. In metastatic cancers, this circulating cell population must also contain at least one cancer stem cell. Since intermittent hypoxia has been proposed as a key player in triggering the epithelial-mesenchymal-transition that is involved with stem cell generation/selection and therapy resistance, the PDAC-on-a-chip offers a new way to isolate stem cell-enriched populations. As far as we are aware, this is the only in vitro device that modulates culture conditions to select/generate and collect cells equivalent to the circulating cancer cell populations observed in vivo. This device will be used to collect cells for the unbiased identification of markers of metastatic cancer and pancreatic cancer stem cells. Identification of these markers could be used to screen patient samples for aggressive PDAC and ultimately provide targets for therapy development. In multiplexed format, this device could also be used to screen for anti-metastic and/or anti-cancer stem cell therapies. PUBLIC HEALTH RELEVANCE: The presence of hypoxia in pancreatic tumors is correlated with poor patient outcome. The proposed project focuses on the development of better in vitro models of tumor hypoxia and metastasis. This new technology will improve the screening of cytotoxic and antimetastatic agents, help find new targets for therapy and aid in the identificatio of relevant biomarkers for aggressive cancer. The overall objective is to improve treatment outcome in pancreatic cancer patients.